Early-onset vascular leukoencephalopathy caused by bi-allelic NOTCH3 variants

Objective Heterozygous NOTCH3 variants are known to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), with patients typically presenting in adulthood. We describe three patients presenting at an early age with a vascular leukoencephalopathy. Genome sequencing revealed bi-allelic variants in the NOTCH3 gene. Methods Clinical records and available MRI and CT scans of three patients from two unrelated families were retrospectively reviewed. Results The patients presented at 9-14 months of age with developmental delay, seizures, or both. The disease course was characterized by cognitive impairment and variably recurrent strokes, migraine attacks, and seizures. MRI findings pointed at a small vessel disease, with extensive cerebral white matter abnormalities, atrophy, lacunes in the basal ganglia, microbleeds and microcalcifications. The anterior temporal lobes were spared. Bi-allelic cysteine-sparing NOTCH3 variants in exons 1, 32 and 33 were found. Interpretation This study indicates that bi-allelic loss-of-function NOTCH3 variants may cause a vascular leukoencephalopathy, distinct from CADASIL.

Recurrent Isolated Sixth Nerve Palsy in Childhood—Review on a Rare Phenomenon

Sixth nerve palsy is an ominous sign in pediatric neurology. Due to the long and tortuous course of the sixth (abducens) nerve, it is generally considered a sign of intracranial pathology. Sixth nerve palsy is associated with increased intracranial pressure and neoplasms, among other less frequent causes. In ∼5 to 15% of cases, no cause can be identified. These cases are classified as idiopathic or “benign” and recovery is typically complete. A recurrence of symptoms is very rare. We provide a rare case report of recurrent benign sixth nerve palsy in a 5-year-old child. In addition, we provide an overview of all earlier published cases of recurrent isolated sixth nerve palsy. To date, only 72 pediatric patients with recurrent isolated sixth nerve palsy have been reported. Young females with left-sided sixth nerve palsy and recent immunization are at risk of recurrence. Pathophysiological mechanisms have been discussed, but have yet to be clarified. Recurrent isolated sixth nerve palsy is only rarely associated with severe causes and the need for extensive investigation may be questioned.

Test–Retest Reliability and Construct Validity of the German Translation of the Gait Outcome Assessment List (GOAL) Questionnaire for Children with Ambulatory Cerebral Palsy

The Gait Outcome Assessment List (GOAL) is a patient or caregiver-reported assessment of gait-related function across different domains of the International Classification of Functioning, Disability, and Health (ICF) developed for ambulant children with cerebral palsy (CP). So far, the questionnaire is only available in English. The aim of this study was to translate the GOAL into German and to evaluate its reliability and validity by studying the association between GOAL scores and gross motor function as categorized by the gross motor function classification system (GMFCS) in children with cerebral palsy (CP). The GOAL was administered to primary caregivers of n = 91 children and adolescents with CP (n = 32, GMFCS levels I; n = 27, GMFCS level II; and n = 32, GMFCS level III) and n = 15 patients were capable of independently completing the whole questionnaire (GMFCS level I). For assessing test–retest reliability, the questionnaire was completed for a second time 2 weeks after the first by the caregivers of n = 36 patients. Mean total GOAL scores decreased significantly with increasing GMFCS levels with scores of 71 (95% confidence interval [CI]: 66.90–74.77) for GMFCS level I, 56 (95% CI: 50.98–61.86) for GMFCS level II, and 45 (95% CI: 40.58–48.48) for GMFCS level III, respectively. In three out of seven domains, caregivers rated their children significantly lower than children rated themselves. The test–retest reliability was excellent as was internal consistency given the GOAL total score. The German GOAL may serve as a much needed patient-reported outcome measure of gait-related function in ambulant children and adolescents with CP.

Epilepsy and Sleep in the ATR-X Syndrome

Background This study explores the prevalence, clinical characteristics, and treatment of epilepsy and sleep disorders in α thalassemia mental retardation (ATR-X) syndrome. Design In this cross-sectional study, 37 participants with ATR-X syndrome aged 1.8 to 44 years were studied using a customized epilepsy questionnaire, review of electroencephalography (EEG) findings, the modified Sleep Questionnaire of Simonds and Parraga and 2-week sleep diary. Results Eleven participants had a clinical diagnosis of generalized epilepsy (29.7%). Seizure types were generalized tonic-clonic seizures, absences, and myoclonia. Interictal EEG recordings in participants with GTCS showed no epileptic discharges in 78%. Similarly, EEG recordings during myoclonia and absences often demonstrated no epileptic discharges. Sleep problems (difficulty falling or maintaining sleep, and early awakening) were reported in 70%. Participants with reported sleep problems went to bed earlier (p = 0.027) and had a lower sleep efficiency (p < 0.01) than participants without sleep problems, but as a group they both had a sufficient total sleep time (9 hours and 52 minutes vs. 10 hours and 55 minutes). Sixteen participants (43.2) used medication to improve sleep (predominantly melatonin n = 10), being effective in only two. Conclusion One-third of participants with ATR-X syndrome had a clinical diagnosis of epilepsy, but the absence of EEG abnormalities in suspected epileptic seizures questions this diagnosis in these patients. EEG recording during seizure like symptoms is warranted before making an epilepsy diagnosis. Seventy percent experienced sleep problems, although total sleep time was normal in most participants. Long bedtimes might have a negative influence on sleep efficiency.

Stiff Person Syndrome and Encephalitis with GAD Antibodies with Severe Anterograde Amnesia in an Adolescent: A Case Study and Literature Review

Antiglutamic acid decarboxylase (GAD65) encephalitis is rare and few pediatric cases have been reported, with variable clinical presentations. A 14-year-old female adolescent was managed in our department. She had been treated for several months for drug-resistant temporal lobe epilepsy and gradually presented major anterograde amnesia with confusion. Upon her arrival at the University Hospital Centre, she showed a classical form of stiff person syndrome. The brain magnetic resonance imaging showed bitemporal hyperintensities and hypertrophy of the amygdala. The blood and cerebrospinal fluid were positive for GAD65 antibodies. At 2 years of immunosuppressive treatment and rehabilitation, the course showed partial improvement of the memory and neuropsychiatric impairment, and epilepsy that continued to be active. GAD65 antibodies are associated with various neurological syndromes, and this presentation combining limbic encephalitis and stiff person syndrome is the first pediatric form published to date; there are also few cases described in adults.

Treatment of Plexiform Neurofibromas with MEK Inhibitors: First Results with a New Therapeutic Option

Neurofibromatosis type-1 (NF1)-associated plexiform neurofibromas (PN) are peripheral nerve sheath tumors that can significantly affect the quality of life. Until recently, surgery was the only treatment for these tumors. However, in most cases, surgery cannot achieve complete tumor removal and carries a high risk of postoperative deficits. Therefore, the recent approval of the MEK inhibitor selumetinib for the treatment of NF1-associated PN provides a long-awaited novel therapeutic option. Here, we report our experience with MEK inhibitor treatment in 12 pediatric NF1 patients with inoperable symptomatic PN. Eight patients received trametinib (median therapy duration 12.13 months and range 4–29 months), and four patients received selumetinib (median therapy duration 6.25 months and range 4–11 months). Volumetric magnetic resonance imaging (MRI) after 6 months of treatment was available for seven trametinib patients (median tumor volume reduction of 26.5% and range 11.3–55.7%) and two selumetinib patients (21.3% tumor volume reduction in one patient and +3% tumor volume change in the other one). All patients reported clinical benefits such as improved range of motion or reduced disfigurement. Therapy-related adverse events occurred in 58.3% of patients and mainly consisted of skin toxicity, paronychia, and gastrointestinal symptoms. Two patients discontinued trametinib treatment after 14 and 29 months when severe skin toxicity occurred and no further reduction of tumor size was observed. In one patient, discontinuation of therapy resulted in a 27.2% tumor volume increase as demonstrated on volumetric MRI 6 months later. Our data show that MEK inhibition is a novel therapeutic approach for inoperable PN with promising results and a manageable safety profile.

Headache in Children and Adolescents: The Association between Screen Time and Headache within a Clinical Headache Population

Background More than half of children and adolescents have experienced headache within the last 3 months. Several risk factors for headache have been identified, including obesity and lack of sleep. The association between screen time and headache in children and adolescents is sparsely investigated. The aim of this study was to assess this association and evaluate if it varied according to headache diagnosis. Method This cross-sectional study was performed at the tertiary pediatric outpatient clinic for headache at Herlev University Hospital. A total of 139 participants who answered a questionnaire on lifestyle factors and their daily living were included. Diagnoses of migraine and tension-type headache (TTH) were made according to the International Classification of Headache Disorders-3. Children with both migraine and TTH were allocated to a mixed headache group. We differentiated between total, leisure, and school-related screen time. Results The mean age was 13.20 ± 3.38 years and 53.2% were girls. Note that 25.2% were diagnosed with migraine without aura, 23.0% migraine with aura, 28.1% TTH, 15.8% mixed headache, and 7.9% had an unclassified headache diagnosis at the time of inclusion. There was no statistically significant difference in screen time across the five headache groups. An association between screen time and headache frequency was found in children with migraine with aura. Conclusion In this study, we investigated the association between screen time and headache in children and adolescents. More screen time was associated with more frequent headaches in children with migraine with aura. Future prospective studies are needed to determine the causality of this association.

A Child Presenting with a Glasgow Coma Scale Score of 13: Mild or Moderate Traumatic Brain Injury? A Narrative Review

Objective The objective of this article was to compare children with traumatic brain injury (TBI) and Glasgow Coma Scale score (GCS) 13 with children presenting with GCS 14 and 15 and GCS 9 to 12. Data Source We searched PubMed for clinical studies of children of 0 to 18 years of age with mild TBI (mTBI) and moderate TBI, published in English language in the period of 2000 to 2020. Study Selection We selected studies sub-classifying children with GCS 13 in comparison with GCS 14 and 15 and 9 to 12. We excluded reviews, meta-analyses, non-U.S./European population studies, studies of abusive head trauma, and severe TBI. Data Synthesis Most children (>85%) with an mTBI present at the emergency department with an initial GCS 15. A minority of only 5% present with GCS 13, 40% of which sustain a high-energy trauma. Compared with GCS 15, they present with a longer duration of unconsciousness and of post-traumatic amnesia. More often head computerized tomography scans show abnormalities (in 9–16%), leading to neurosurgical intervention in 3 to 8%. Also, higher rates of severe extracranial injury are reported. Admission is indicated in more than 90%, with a median length of hospitalization of more than 4 days and 28% requiring intensive care unit level care. These data are more consistent with children with GCS 9 to 12. In children with GCS 15, all these numbers are much lower. Conclusion We advocate classifying children with GCS 13 as moderate TBI and treat them accordingly.

Validity and Reliability of the German Version of the CP QOL-Child and CP QOL-Teen Questionnaire

The aim of the study was to determine the psychometric properties of the German version of the Cerebral Palsy Quality of Life Questionnaire for Children and Adolescents (CP QOL-Child and -Teen). It is a condition-specific questionnaire with a self-report version, measuring well-being rather than ill-being, which differs from existing measurement methods. Fourteen children (9–12 years) and 64 caregivers (4–12 years) answered the child questionnaire. Twenty-one adolescents and 26 caregivers (all adolescents 13–18 years) replied to the teen version. Functioning was categorized by the Gross Motor Function Classification System. For CP QOL-child internal consistency (Cronbach's α) ranged from 0.58 to 0.88 and for CP QOL-Teen from 0.68 to 0.95. Test–retest reliability after 2 to 4 weeks ranged between 0.75 and 0.94 in children's version and 0.89 and 0.96 in teen's version. Correlation with well-established generic KIDSCREEN-10 questionnaire was moderate to strong. The German versions of CP QOL-Child and -Teen are appropriate tools for assessing the quality of life of children and adolescents with cerebral palsy in the German-speaking population.